SUMMARY Prostate Cancer (PCa) is the second-leading cause of cancer-related deaths in American men. The morbidity and the mortality to PCa are 2.44-fold higher in African American men as compared to Caucasian counterparts. Therapies such as surgery, radiation and androgen-ablation have been developed to control PCa for patients at different stages. However, the relapse of this disease is reported in many cases, particularly in patients at advanced stage-metastasis, and as a result patients eventually died of the recurrent growth of castration resistant prostate cancer (CRPC). Studies demonstrated that various alterations of tumor suppressors and oncogenes contribute to the initiation and progression of PCa as well as the recurrent growth of CRPC. Emerging evidence revealed that CRPC growth is a complicated malignancy with dysregulation of multiple oncogenic pathways. Mechanisms on the oncogenic signaling pathways leading to CRPC are poorly understood, and their aberrant activations are regulated in a context and environment dependent manner. Yet, it is urgent to explore novel drugs and further to develop efficient treatments in order to reduce the incidence and mortality rate of PCa and to eliminate the disparities among ethnic groups. Aberrant elevation of SKP2 and AR are frequently found in advanced PCa and CRPC. We discovered that SKP2 inactivation partially suppresses PCa progression but also leads to aberrant elevation of AR and FOXA1 pathways. We HYPOTHESIZE that AR elevation confers resistance to SKP2 inhibition in prostate cancer cells and a combined inhibition of SKP2 and AR can effectively suppress the CRPC growth. We propose to test this hypothesis by evaluating the molecular profiling of FOXA1/AR regulated by SKP2, the anti-proliferation effects of co-targeting SKP2 and AR in PCa cells in vitro and its efficacy of combined treatment on the suppression of prostate tumors in mice in vivo. The following specific aims are proposed: 1) Define the mechanisms on the regulation of FOXA1/AR pathways by SKP2 in PCa cells; 2) Study the molecular profiling of FOXA1/AR signaling by SKP2 in PCa cells; and 3) Investigate the efficacy of combined targeting of SKP2 and AR inhibition on the suppression of PCa progression in vivo. Results will provide a novel and efficient therapeutic regimen to suppress CRPC growth.